2-methyl steroids and process



2,865,935 Z-METHYL STEROIDS AND PROCESS William P. Schneider, Frank H. Lincoln, and John A.

Hogg, alamazoo Township, Kalamazoo County,

ich., assign'ors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan No Drawing. Application November 16, 1955 Serial No. 547,310

16 Claims. c1; zoo-397.45

The present invention relates to novel steroid compounds and is more particularly concerned with 2-loweralkyl-l l-oxygenated 17u-hydroxyprogesterones selected from the group consisting'of 2-loWer-alky1-l1,8,17a-dihydroxy-4-pregnen'e-3,ZO-dione, 2-l0wer-alkyl-17a-hydroxy- 4-pregnene-3,11,20-trione, 2-lower-alkyl-9a-halo-115,170:- dihydroXy-4-pregnene-3,20-dione and 2-loWer-alkyl-9uhalo-17rx-hydroXy-4-pregnene-3,l1,20-trione wherein the halo atom has an atomic Weight between 17 and 131 and wherein the lower-alkyl radical contains from one to eight carbon atoms, inclusive. 4 The novel compounds of the present invention and the process for their production may be represented by the following formulae:

LI'JHQQAO' lower- I alkylv II I loweralkyl one;

loweralkyl lower alk yl wherein R is selected from the group consisting of hydrogen and halogen of atomic weight between -17- and 131,

wherein lower-alkyl contains fromone to' eight'carbon atoms, inclusive, and wherein Ac isthe acyl' group of an organic carboxylic acid, preferably a hydrocarbon car:

2,865,935 Patented Dec. 23, 1958 2 v boxylic acid containing'i fromone to eight carbon atoms, inclusive. t a I The process, of the instant invention comprises reacting a 2-lower-a1kyl-l1 fi,1701,21-trihydroxyprogesterone (II) invention to provide 2 -l0WBr-alkyl-I 1a,17 dihydroxy-4-pregnene 3,20 dione,

2-lower-alkyl 17a-hydroxy-4-pregnene-3,l1,20 trione, 2 loweralkyl-9a-halo- 11fi, 17o-dihydroxy- -pregnene 3,20- dione and 2-lower-alkyl-9a-halo-17a-hydroxy-4 pregnene- 3,11,20-trione. Itisa further object of the instant inven- CHzOH H0 H0 nit, on,

tion to produce '2-me'thyl-l 1,8,17d-dihydroxy=4-pregiiene 3,20-dione, 2-m'ethyl-17a hydrox-y#4 pregnene 3, l"1',20-trione and the 9a-fluoro derivatives thereof." Other objects will be apparent to thoseiskilled intheart'to which this invention pertains;

The novel 2-lower-alkyl-l l13,17a-dihydroxy-4-pregnene- 3,20-diones, the 2-lower-alkyl-l7a-hydroxy-4-pregnene-3, 11,20-triones and the corresponding 9a-halo compounds especially the 9a-fiuoro compounds possess a high order of physiological activity, and possess activity spectra different from the adrenalcortical hormones found in nature such as hydrocortisone and cortisone. The novel synthetic corticosteroid hormones of the present invention possess anti-inflammatory, glucocorticoid, anesthetic, uterine, ovarial and adrenal growth-depressional, and adrenal corticoid activity. The anti-inflammatory activity is especially noticeable in all the steroids of the present invention.

The novel 2-lower-alkyl-l1)8,17a-dihydroxy-4-pregnene- 3,20-diones and Z-lower-alkyl-17m-hydroxy-4-pregnene-3, 11,20-trione are useful in oral compositions as well as in topical applications. In oral compositions the material may be given as'tablets illustratively using either polyethylene glycol 4000 or 6000 as a carrier or lactose and/or sucrose and a diluent. The novel 2-lower-alkyl- 1 1p,17wdihydroxy-4-pregnene-3,20-dione, 2-lower-alkyl- 17u-hydroxy-4-pregnene-3,l1,20-trione and their 9e-halo derivatives are especially useful for topical application as ointments, lotions, jellies, creams, aqueous suspension etc. Examples of especially advantageous topical preparations of suitable compositions are given below. The examples are to the Z-methyl-llfi,l7o -dihydroxy-4-pregnene-3,20-dione and Z-methyl-l7a-hydroxy-4-pregnene-3, 11,20-trione as well as the 9a-fiuoro derivatives thereof; however, equivalent amounts of the other 2-lower-alkyl homologues and corresponding 9a-chloro, bromo or iodo analogs of this invention respectively are substitutable therein.

A suitable dermatological and ophthalmic ointment has the following composition:

Lbs. Wool fat, USP 100 Mineral oil, USP 125 2-methyl-l1B,l7a-dihydroxy-4-pregnene-3,20 dione (micronized) 7 White petrolatum, USP S Incorporation of an antibiotic in the ointment, especial ly neomycin sulfate, has therapeutic advantages each active ingredient potentiating and supplementing the useful properties of the other. Such an ointment is as follows:

- Lbs. Wool fat, USP 100 Mineral oil, USP 125 Neomycin sulfate 3 2-methyl-9a-fluoro-l 15,17u-dihydroxy-4-pregnene 3,

ZO-dione (micronized) 3.5 White petrolatum, USP 500 In place of, or in addition to, neomycin sulfate, other antibiotics such as bacitracin, circulin, polymyxin B sulfate, gramicidin, streptomycin sulfate, dihydrostreptomycin sulfate, oxytetracycline, chlorotetracycline, tetracycline, chloramphenicol and the sulfonamides can be used in conjunction with the steroids of the present invention in preparations such as the above ointments.

The compounds of the instant invention, Z-methylll ,8,l7a-dihydroxy-4-pregnene-3,20- dione, the 11 keto compounds and the corresponding 9e-halo derivatives are also useful as starting materials for the preparation of other physiological important compounds. For example, 1 15,17fl-dihydroxy-2,17a-dimethyl-4-androstene-3-one can. be produced from 2-methyl-11B,17m-dihydroxy-4-pregacne-3,20 dione by reduction in aqueous methanol solution with sodium borohydride to obtain first the Z-methyl- 301,11 l8,l7a,20-tetrahydroxy-4-pregnene, splitting off the 4-androstene-17-one which by treatment with methyl magnesium bromide produces the 2',17-dimethyl'-- 3,11 3,17,6-trihydroxy-4-androstene which by oxidationwith manganese 2,17-dimethyl-4-androstene-3-one of high anabolic activity.

The starting materials in the instant invention, 2-lower-- alkyl-l 1B,17ot,2l-trihydroxy-4-pregnene-3,ZO-dio-nes and 2-- lower-alkyl-17:1,21-dihydroxy-4-pregnene- 3,11,20 triones are obtained by hydrolysis of the respective Zl-organic carboxylic acid esters (Preparations l-8) thereof. To obtain the above named free steroid alcohols the selected 2-lower-alkyl-l1,8,l7a-dihydroxy-2l-acyloxy -4- pregnene 3,20-dione, 2-lower-alkyl-l7a-hydroxy-21-acyloxy-4-pregnone-3,11,20-trion'e or the 9uc-h3l0 derivatives thereof are subjected to acid or basic hydrolysis. In case of an acid hydrolysis which is preferred for those 2-lower-alkyl- 1118,l7a-dihydroxy-4-pregnene-3,20-diones possessing in the 9a-position a chloro, bromo, or iodo compound, the compound is dissolved in an organic solvent such as methanol, ethanol, propanol, tertiary butyl alcohol, dioxan'e, acetone, dimethyl formamide, or the like, in the presence of some water, and treated with a small quantity of a strong mineral acid such as hydrochloric, sulfuric, chloric, perchloric, or a strong benzene-sulfonic acid such as toluenesulfo-nic acid, chlorobenzene-sulfonic acid, B naphthylsulfonic acid, or the like. The reaction is effected at a temperature between zero degrees and the boiling point of the reaction mixture, preferably between room temperature and a slightly elevated temperature such as to degrees centigrade. The proportion of mineral acid in the solvent is usually low and varies between 0.25 to five parts of acid for 100 parts of solvent by weight. The time of reaction varies between one hour and 120 hours depending on the concentration of acid, the temperature at which the reaction is carried out and the type of acyl group to be removed. Mild conditions are preferred since high temperatures and high acid concentration produce partial dehydration of the llp-hydroxyl group. After the reaction is terminated the material is isolated by a stand ard procedure such as pouring the reaction mixture in excess of water, neutralizing and collecting the precipitate of material on a filter.

Purification of the thus produced crude Z-lower-alkyh 1lB,l7a,2l-trihydroxy-4-pregnene-3,20-dione is achieved ,by conventional means such as extracting the impurities,

i chromatography or recrystallization using organic solvents side-chain by using periodic acid, or by a microbiological fermentation procedure employing fungi of the genus- Penicillium, for example, Penicillium lilacinum, or fungi however, higher or lower temperatures such as methyl alcohol, ethyl alcohol, Skellysolve B hexanes, acetone, benzene, chloroform, dichloroethylene, methylene chloride, mixtures of these or the like, as deemed convenient. H

Hydrolysis of the 2-lowcr-alkyl-1lfi,l7a,2l-trihydroxy- 4-pregnene-3,20-dione 2l-acylate, 9u-fill0f0 derivatives thereof, the 2-lower-alkyl 1l{3,17a-dihydroxy-4pregnene- 3,11,20-triones ZI-acylates and 9a-halo derivatives thereof, can be performed in a basic medium. In this case the selected steroid is dissolved in an organic solvent, preferably an organic solvent miscible with water such as methanol, ethanol, propanol, tertiary butyl alcohol, dioxane, or the like, and thereto is added a base such as sodium hydroxide, potassium droxide, aqueous ammonia, potassium or sodium bicar bonate, potassium or sodium carbonate, or the like. the preferred embodiment of the invention the steroid solution is protected from atmospheric oxygen by using an atmosphere of nitrogen during the reaction. The solution is first saturated withnitrogen gas before the addi tion of the base. The preferred bases are the milder ones such as sodium bicarbonate or potassium bicarbonate. The reaction is suitably performed at room temperature, that is between fifteen to thirty degrees centigrade; are operative. the reaction is between one-half hour to 24 the temperature selected, the depending on the type of acyl radical The time for hours depending on of base selected, and

dioxide produces 1l 8,17,B-dihydroxyamount on the ZI po-sitio'n ofthe selected steroid; The proportion of base used is usually in excess of that theoretically required, i. e., one mole of base per mole of steroid estm. However, to prevent undesirable side reactions the proportion of base used is generally restricted to between" one mole of steroid to one mole of base and about three moles of base to one mole of steroid. After the reaction is terminated, the solution is neutralized with an acid, such as dilute hydrochloric, dilute sulfuric, or acetic acid and t e product is thereupon removed by conventional procedures such as extraction, evaporating the solvent and washing the residue thus obtained with water to remove Water-soluble salts, or drowning the reaction mixture in excess of water and refrigerating the aqueousreaction mixture to collect the resulting solid precipitatde. The solid precipitate is purified by conventional means such as recrystallization, extraction of impurities or chrornatography using organic solvents such as acetone, Skellysolve B hexanes', ethyl acetate, methanol, ethanol, dioxane, or the like, as deemed necessary.

In carrying out the process of the present invention, 2- lowcr alkyl-l1 3,17a,21 trihydroxy-4-pregnene-3,ZO-dione or the S d-halo derivative thereof is esterified with an organic sulfcnic acid such as toluenesulfonyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, substituted benzenesulfonyl chloride, such as o-rtho-, meta-, or para chlorobenzenesulfonvl chloride, the ortho-, meta-, or para-nitrobenzenesulfonyl chloride, benzenesulfonyl chlorides substituted by other halo, nitro, methoxy, ethoxy, and the like groups, or the like, with toluenesulfonyl chloride preferred. The esterification is carried out in solution using pyridine or neutral solvents such as benzene, toluene, chloroform or the like as the solvent. The amount of reactant, an organic acid sulfonyl chloride,

solvent such as methylene chloride, benzene, chloroform, carbon tetrachloride, or the like, while stirring the reaction Thereafter the product a 2- methyl-l 1,8,17u-dihydroxy-21-organic sulfonyloxy-4-pre nene-3,20-dione is isolated by conventional means,

sulfonate of the thus obtained 2-methyl-11/3,17a,21-trihydroxy-4-pregnene-3,ZO-dione. The crude product may be used for the subsequent reaction.

The organic acid sulfonate of Z-IOWtEf-EllkYl-l1B,17oc,21- trihydroxy-4-pregnene-3,ZO-dione, dissolved in acetone, is treated with an excess of alkali metal iodide vents such as acetone, ethanol, methanol, hexanes, or the like, to give pure 2-lower-alkyl-11B,17udihydroxy-Z1-iodo-4-pregnene-3,20-dione.

For the reduction procedure either the crude or the recrystallized 2 lower alkyl-l1,6,l7a-dihydroxy-21-iodo-4- filtrate is isolated the corresponding 2 lower alkyl-l1fl,17a-dihydroxy-4 pregnene-3,20-dione by conventional means, e. g., neutralizing crude 2-lower-alkyl- 11,8,17a dihydroxy 4--pregnene-3,20-dione. The crude crystalline material may be purified by conventional means such as recrystallization, additional extractions of impurities, or chromatography as deemed necessary.

The thus obtained 2-methyl-11B,17a-dihydroxy-4- pregnene-3,20-dione, if so desired, is converted to 2- methyl-l7a-hydroxy-4-pregnene-3,l1,20-trione by oxidation with chromic acid in either a homogeneous or heterogeneous medium. in a homogeneous medium the re action is carried out by dissolving the selected steroid in percent, Water present in commercial grades of acetic acid may be sufficient for chromic acid produced oxidation, otherwise if high-grade glacial acetic acid has to ten percent of water should be added. is usually carried thirty degrees with temperatures between five and fifteen degrees preferred. however, operative. time of reaction in the preferred condition is between two and sixv hours. Agitation is usually used and is preferred in the instant procedure.

Using a heterogeneous medium for the oxidation, the dissolved in a water-immiscible solvent tween fifteen and thirty degrees; higher temperatures are operative. varies between one and twelve hours matography as deemed necessary.

Instead of undertaking the oxidation as the last step PREPARATION 1 Z-glyoxalation of 11B-hydroxy-21-ncet0xy-4,17(20)- pregnadiene-S-oie A solution of 18.62 grams (0.05 mole) of llfi-hydroxy- 2l-acetoxy-4,17(20)-pregnadiene-3-one was prepared in 300 milliliters of dry tertiary butyl alcohol by heating the mixture at seventy degrees centigrade. The solution was cooled to 55 degrees centigrade and to the stirred solution, protected from atmospheric oxygen by bubbling nitrogen therethrough, was added 11.5 grams (0.10 mole) of methyl oxalate followed by a solution of 4.05 grams (0.075 mole) of sodium methoxide dissolved in sixteen milliliters of methanol. A thick, pale yellow precipitate soon appeared. Stirring was continued for ten minutes and the mixture was then diluted with 300 milliliters of anhydrous ether. Stirring was continued for an additional fifteen minutes and the mixture then filtered. The pale yellow-green precipitate was washed and dried at room temperature in a vacuum. The yield of about 24 grams of precipitate consisted primarily of a sodium enolate of 2-methoxyoxalyl-1lfi-hydroxy-21-acetoxy-4, 17(20)-pregnadiene-3-one.

The precipitate was dissolved in 250 milliliters of water and the solution acidified with dilute hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried. There was thus obtained 18.71 grams of an amorphous powder consisting essentially of Z-methoxyoxalyl-llfi-hydroxy-Zl-acetoxyl,17 (20)-pregnadiene-3-one which melted at eighty to 95 degrees centigrade and which gave a positive red-brown ferric chloride test.

PREPARATION 2 Z-forinylaiion of 1 1 fl-hydroxy-ZI -acetoxy-4,1 7(20) pregnadiene-Z-one A mixture of 150 milliliters of dry benzene and a solution of 8.10 grams (0.015 mole) of sodium methoxide in 33 milliliters of methanol was distilled in a nitrogen atmosphere until sixty milliliters of distillate was collected.

7 The remaining suspension of sodium methoxide in benzene was cooled to fifty degrees centigrade and 18.5 grams (0.25 mole) of ethyl formate was then added. After stirring the mixture for fifteen minutes, a solution of 3 -keto-l 1B-hvdroxy-21-acetoxy-4, 1 7 (20) -pregnadiene- 3-one in 300 milliliters of dry benzene at fifty degrees centigrade was rapidly added thereto. The temperature of the mixture was gradually reduced to about 25 degrees centigrade while stirring was continued for one hour. There was then added 250 milliliters of anhydrous ether followed by further stirring for an additional hour whereafter another 250-milliliter portion of ether was added and the mixture was maintained at about 25 degrees centigrade for about sixteen hours. The resulting precipitate, consisting essentially of the sodium enolate of 2-tormyl-1 lfi-hydroxy-21-acetoiry-4,17(20) -pregnadiene-3-one first appeared as a gum but solidified upon standing. To the stirred mixture was then added 500 milliliters of water andthe stirring contiued until all of the solid had dissolved. The aqueous layer was separated, washed with ether and then acidified with dilute hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried. There was thus obtained 12.14 grams of a mixture consisting essentially of Z-iormyl-llfl-hydroxy-Zl acetoxy 4,170.0)- pregnadiene-3-one which melted at 110 to 123 degrees centigrade and which gave a positive deep violet ferric chloride test.

Following the procedure described in Preparation 2, other 2l-esters of 2-formyl-1lfl,21-dihydroxy-4,l7(20)- pregnadiene-3-one are prepared by substituting the corresponding Zl-ester of llB,2l-dihydroxy-4,17(20)-pregnadiene-3-one as the starting steroid of the reaction described in Preparation 2. Examples of Z-fOrmyl-llB-hydroxy-2]-acyloxy-4,l7(20)-pregnadiene-3-ones thus prepared include those wherein the acyl group is the acyl radical of a lower-aliphatic acid, e. g. formic, propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, hexanoic, heptanoic, diethylacetic, triethylacetic and octanoic.

PREPARATION 3 Z-methyZ-Z-methoxyoxalyl-I 1 fl-hydroxy-ZI-acetoxy- 4,1 7(20)-pregnadiene-3-0ne A mixture of 4.70 grams of crude Z-methoxyoxalyl- 1lfl-hydroxy-Zl-acetoxy-4,l7(20)-pregnadiene-3-one, obtained according to the method of Preparation 1, ten grams of anhydrous potassium carbonate, fifteen milliliters of methyl iodide and milliliters of acetone was stirred at about 25 degrees centigrade for forty hours. Water was then added and the mixture extracted thoroughly with methylene chloride. The extract was washed with water, dried and the solvent distilled to leave a glassy residue consisting essentially of 2-methyl-2-methoxyoxalyl-llfl-hydroxy-Zl-acetoxy4,17(20) pregnadiene-3-one.

Similarly, other 2-lower-alkyl-2-alkoxyo-xalyl-llB-hy droxy-2i-acyloxy-4,l7(20)-pregnadiene-3-ones are prepared by reacting a 2-alkoxyoxalyl-l1(3-hydroxy-2l-acyloxy-4,l7(20)-pregnadiene-3-one with an alkyl halide, e. g., methyl bromide, ethyl bromide, propyl bromide, butyl bromide, amyl bromide, hexyl bromide, hcptyl bromide, octyl bromide, phenyl bromide or benzyl iodide, to produce the corresponding Z-alkylated product wherein the alkoxy and acyloxy groups correspond to those of the starting Z-alkoxy-oxalyl-l lfi-hydroxy 21 acyloxy 4,17 (20)-pregnadiene-3-one and the alkyl group corresponds to that of the alkyl halide, e. g., Z-methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, phenyl, benzyl, etc., 2- methoxy, ethoxy, propoxy, butoxy, amyloxy, hexyloxy, heptyloxy, octyloxyoxalyl, etc, and 21-formyloxy, acetoxy, propionylo-xy, butyryloxy, valeryloxy, hexanoyloxy, hep tanoyloxy or octanoyloxy.

If the starting 2-allcoxyoxalyl steroid to be alkylated is 2l-esterificd, the reaction product, depending upon the ease of hydrolysis of or alcoholysis of the 2l-ester group and the alkylation conditions, produces a reaction product consisting, at least in part, of 2-alkylated steroid having a 21-hydroxy group. Examples of 21-ester groups quite resistant to hydrolysis or alcoholysis are 2l-trimethylacetate and ZI-triethylacetate. Other Ill-esters may, if the alkylation reaction contains methyl or ethyl alcohol, be partially or completely converted to a 2l-hy droxy group.

PREPARATION 4 The glassy residue of crude Z-methyl-Z-rnethoxyoxalyl- 1lfi-hydroxy-Zl-acetoxy-4,17(20)-pregnadiene-3-one, obtained according to the method described in Preparation 3, was dissolved in fifty milliliters of methanol to which was then added three milliliters of a 25 percent solution of sodium methoxide in methanol. The now red solution was stirred for two hours at about 25 degrees Centigrade. The mixture was then diluted with about 200 milliliters of water and extracted thoroughly with methylene chloride. The combined methylene chloride extracts were washed with water, dried, and the solvent then dis tilled therefrom, leaving a steroidal residue consisting essentially of Z-rnethyl-l15,2l-dihydroxy-4,17(20)-pregnadiene-3-one. The thus-produced 2-methyl-1lB,2l-dihydroxy-4,1?(20)-pregnadiene-3-one is purified by chroma tography over Florisil synthetic magnesium silicate using Skellysolve B hexane hydrocarbons "containing increasing amounts of acetone-for development.

Similarly, 2-methyl-1118,2l-:iihydroxy-4,1'7(20)-pregnadiene-3-one is prepared by substituting, as starting steroid for the reaction described above, another 2-methyl-2- lower-alkoxyoxalyl-l lfl-hydroxy 21 acetoxy 4,l7(20)- pregnadiene-3-one, e. g., wherein the lower alkoxy group is ethoxy, propoxy, butoxy, amyloxy, hexyloxy, heptyloxy or octyloxy, for the Z-methyl-2-rnethoxy-oxalyl-llB-hydroxy-Z 1-acetoxy-4, 17 (20)-pregnadiene-3-one employed in Preparation 4.

Following the procedure described in Preparation 4, other 2-lower-alkyl-1118,2l-dihydroxy 4,.17(20) pregnadiene-3-ones are prepared wherein the lower-alkyl group is, for example, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, phenyl, benzyl, etc., by substituting a 2-loweralkyl-2-lower-alkoxyoxalyl-l113,21 dihydroxy 4,17(20)- pregnadiena-3-one or 21-acyloxy ester thereof wherein the lower-alkoxy group is, for example, methoxy, ethoxy, propoxy, butoxy, amyloxy, exyloxy, heptyl'oxy, etc., and the lower-alkyl group corresponds to the desired lower-alkyl group of the reaction product, for the 2-methyl-2 methoxyoxalyl 11B hydroxy 21 acetoxy- 4,l7(20)-pregnadiene-3-one employed as starting steroid in the reaction described in Preparation 4.

PREPARATION 5 Z-ethyl-I 15,2] -dihydr0xy-4,I 7 20) -pregnadiene-3-one PREPARATION 6 2-methyZ-1 JB-hydroxy-ZI -acet0xy-4,I 7 (20 -pregnadz'ene-3-one The crude residue obtained from Preparation 4, 2- methyl-l lB,21-dihydroxy-4,l7(20)-pregnadiene 3 one, was dissolved in a mixture of ten milliliters of acetic anhydride and ten milliliters of dry pyridine. The mixture was maintained at about 25 degrees centigrade for about sixteen hours. The excess acetic anhydride was then decomposed with ice water and the resulting gummy precipitate was extracted with benzene. The benzene solution was washed with cold dilute hydrochloric acid, cold aqueous sodium bicarbonate and finally with water and then dried. The dried benzene solution was poured over a chromatographic column of 100 grams of Florisil synthetic magnesium silicate. The column was developed with 1350 milliliters of Skellysolve B hexane hydrocarbons containing five percent acetone followed by 750 milliliters of Skellysolve B plus 7.5 percent acetone and then 150 milliliters of acetone. The eluates were collected in 150 milliliter fractions. Eluate fractions 4 to 8 contained a total of 1.71 grams, a yield of 44 percent, calculated on the starting Z-methoxyoxalyl- 11/3,21-dihydroxy-4,17(20)-pregnadiene-3-one, of crystalline Z-m-ethyl-l 1 ,B-hydroxy-Zl-acetoxy-4,17( 20) pregnadiene-3-one. Recrystallization of this product gave pure 2-methyl-11B-hydroxy-21-acetoxy-4,17(20) pregnadiene- 3-one of melting point 182 to 184.5 degrees centigrade, having a [0:1 of plus 145 degrees in chloroform, an ultraviolet adsorption of 15,025 at 242 millimicrons and the analysis below.

Calculated for C H O C, 74.57; H, 8.87. Found: C, 74.32; H, 8.79.

Similarly, 2-methyl-1 1,8,21-dihydroxy-4,17(20)-pregnadiene-3-one is converted to other 2-methyl-l1 8-hydroxy- 21-acyloxy-4,17(20)-pregnadiene-3-ones by esterification of the 21-hydroxy group, e. g., by reaction with the appropriate acid anhydride, acid chloride or bromide, ester by ester exchange, acid in the presence of an esterification catalyst, etc., Z-methyl-l1,8,21-dihy.droxy-4,17

1 f(20)-pregnadiene'-3-one is similarly converted to other 21-esters thereof. Examples of 2-methyl-llfi-hydroxy- 2l-acyloxy-4,l7(20)-pregnadiene-3-one prepared include those wherein the acyl group is the acyl radical of, for example, a lower-aliphatic acid, e. g., formic, propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, 3-ethylbutyric, hexanoic, diethylacetic, triethylacetic, heptanoic, octanoic, the optically active abietic, a-ethylisovaleric, an acyclic acid, e. g., 3,8-hydroxycholanic, 3fi-hydroxyeti0cholanic, cyclopropylideneacetic, a cycloaliphatic acid, e. g., cyclopentylformic, cyclopentylacetic, fl-cyclopentylpropionic, cyelohexylformic, cyclohexylacetic, fl-cyclohexylpropionic, an aryl, or alkaryl acid, e. g., benzoic 2,3 or 4-methylbenzoic, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimcthylbenzoic, ethylbenzoic, 2,4,6-trimethylbenzoic, 2,4,6-triethylbenzoic, oc-llflPhihOiC, S-methyl-a-naphthoic, an aralkyl acid, e. g., phenylac-etic, phenylpropionic, diphenylacetic, triphenylacetic, a dibasic acid (which can be converted to 'water soluble, e. g., sodium salts), e. g., succinic, glutaric, a-methylglutaric, B-methylglutaric, ,8, -dimethylglutaric, pirnelic, suberic, a hydroxyacid, e. g., glycolic, lactic, citric, tartaric, d-maleic, d-glyceric, mannonic, gluconic, salicylic, an aminoacid, e. g., glycine, diglycollamic, triglycollamic, methylglycine, dimethylglycine, di-ethylglycine, para-aminosalicylic, para-aminobenzoic, other hetero-substituted acids, e. g., ethylmercaptoacetic, benzylmercaptoacetic, cyanoacetic, chloroacetic, fluoroacetic, trichloroacetic, trifiuoroacetic, thioglycolic, 2,3,4-trimethoxybenzoic, a-naphthoxyacetic, fl-pyrrolidylpropionic, carbamic acids, e. g., carbamic acid, phenylcarbamic, n-butylcarbamic, dimethylcarbamic, diethylcarbamic, allophanic, or a heteroeyclic acid, N-methylpyrrolidyl-Z-carboxylic,

a-picolinic, indole-Z- PREPARATION 7 Z-ethyl-J 1 B-hydrox'y-Z] -acet0xy-4,1 7 20) pregnadiene-3 0ne in methylene chloride and poured over a column of Florisil synthetic magnesium silicate. The 2-ethyl-ll,8- hydroxy-Zl-acetoxy-4,17(20) pregnadiene 3 one was mixture of acetone and Skellysolve B, at 149 to 151 degrees centigrade, and had the analysis below.

Calculated for (3 1-1 0 C, 74.96; H, 9.06. Found: C, 75.23; H, 9.17.

Similarly, other 2 lower alkyl 1113,21 dihydroxy- 4,17(20)pregnadiene-3-ones are esterified to produce the 2-lower-al kyl-l1fi-hydroxy-21-acyloxy-4,17(20)-pregnadiene-3-ones wherein the lower-alkyl group is, for example, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl,

following. 7

PREPARATION 8 Z-methyl-J1B,]7a-dihydroxy-21-acet0xy-4-pregnene- 3,20-dione To a solution or" 1.40 grams (3.68 millimoles.) of 2- rnethyl-llB-hydroxy 21 acetoxy 4,17(20) pregnadiene-S-one in seventy milliters of dry tertiary butyl alcohol was added at room temperature nine milliliters of dry pyridine, 5.8 milliliters of dry tertiary butyl alcohol solution containing 1.37 grams (9.1 millimoles) of N- e. g., ,B-furylcarboxylic,

methylmorpholineoxide peroxide, and ten milligrams of osmium tetroxide, in that order. The resulting solution was stirred at between 25 and thirty degrees centigrade for eighteen hours. There was then added 150 milliliters of water to the mixture which was thenextracted thoroughly with methylene chloride, the methylene chloride solution washed with water, cold dilute hydrochloric acid, cold aqueous sodium bicarbonate, water andthen dried. The solvent was distilled from the dried solution at reduced pressure. The crude residue was dissolved in methylene chloride and poured over a column of 110 grams of Florisil synthetic magnesium silicate. The column was developed with 175-milliliter portions of solvent of the following composition and order: eight of Skellysolve B plu ten percent acetone, seven of Skeliysolve B plus twelve percent acetone, two of Skellysolve 8 plus fifteen percent acetone, and one of acetone. The Skellysolve B plusfive percent acetone eluted 331 milligrams of starting steroid. The Skellysolve B plus twelve percent acetone eluted 784 milligrams, a yield of 69 percent calculated on the starting steroid which reacted, of Z-methyl-llit-3,17a-dihydroxy- 21-acetoxy-4-pregnene-3,20-dione which, after crystallization from ether, melted at 133 to 135 degrees centigrade, had a [db of plus 158 degrees in chloroform and an analysis as follows:

Calculated 01' (22411340 C, 68.38; H, 8.52.

Subsequent crystallization of 2-metl'1yl-11fi,17a-dihydroxy-21-acetoxy-4-pregnene-3,20-dione from a mixture of ethyl acetate and Skellysolve 13 gave crystals of a different crystalline structure melting at 171 to 171.5, having a [th, of plus 164 degrees, an E of 15,125, the same papergram and infrared spectrum analysis as above and a carbon-hydrogen analysis substantially as calculated.

In the same manner other Z-methyl-llfl-hydroxy-Zlacyloxy-4,17(20)-pregnadiene-3-ones are converted to the corresponding 2-methyl-l15,17a-dihydroxy-2l-acyloxy-4-pregnene-3,20-diones wherein the acyl group is the acyl radical of, for example, a lower-aliphatic acid, 6. g., formic, propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, 3-ethylbutyric, hexanoic, diethylacetic, triethylacetic, heptanoic, octanoic, benzoic, and others as mentioned in Preparation 6.

PREPARATION 9 Z-ethyl-I 1 [3,17a-dihydr0xy-2 I -acetoxy-4-pregnene- 3,20-di0ne Following the procedure described in Preparation 8, but substituting Z-ethyl-l lfl-hydroxy-Z1-acetoxy-4,17(20)- pregnadiene-3-one as the starting steroid, there is thusproduced Z-ethyl-l15,17u-dihydroxy-21-acetoxy 4 pregnene-3,20-dione. The crude reaction product from the oxidative hydroxylation was dissolved in methylene chloride which was poured over a column of Florisil synthetic magnesium silicate. The column was developed in exactly the manner described in Preparation 8 and the 2- ethyl-116,17u-dihydroxy-2l-acetoxy 4 pregnene 3,20- dio-ne, was eluted with Skellysolve B plus ten percent acetone and melted, after crystallization from dilute melthanol, at 166 to 169 degrees centigrade.

Similarly, other 2-lower-alkyl-llfi-hydroxy-Zl-acylx -4,17(20)-pregnadiene-3-ones are oxidatively hydroxylated to produce a compound named in Preparation 8 or the paragraph following wherein the Z-methyl group is replaced by a lower-alkyl group for example, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, phenyl, benzyl, etc.

PREPARATION 10 (2.3 8 millimoles) of 2- C, 68.87; H, 8.19. Found:

-A mixture of one gram methyl-llfhlh-dihydroxy 21 acetoxy 4 p'regrien'ei- 3,20-dione, 662 milligrams (two equivalents) of N- bromoacetamide and six milliliters of pyridine was stirred in the dark for thirty minutes. The mixture was cooled in an ice-water bath and a stream of sulfur dioxide was directed onto the surface of the stirred mixture until a negative potassium iodide-starch test was obtained. Fifty milliliters of water was then added to the mixture and the mixture was maintained at about five degrees centigrade for thirty minutes. The precipitated white solid was filtered, washed wtih water and dried under vacuum. After crystallization from acetone there was obtained 0.82 gram, a yield of percent of the theoretical, of 2- methyl-l7a-hydroxy-2l acetoxy 4,9(11) pregnadiene- 3,20-dione as colorless needles melting at 212 to 217 degrees centigrade. A sample recrystallized from a mixture of acetone and methylene chloride melted at 220 to 223 degrees centigrade, had a [0:1 of plus 138 degrees in chloroform, an infrared adsorption spectrum consistent with the structure, and the analysis below:

Calculated for C I-1 0 C, 71.97; H, 8.05. Found: C, 72,05; H, 8.32.

Following the procedure described in Preparation 10, but substituting another Zl-ester of a 2-lower-alkyll13,17m,21-trihydroxy-4-pregnene-3,20-dione, as shown in Preparations 8 and 9, the 2-methyl-11B,17a-dihydroxy-21-acyloxy-4-pregnene-3,20-diones wherein the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, as the starting steroid in the reaction, there are produced other 21-esters of 2-methyl-17 x,21-dihydroxy-4,9(1l)-pregnadiene-3,20-dione and 2-lower-alkyl homologues thereof.

PREPARATION 1'1 2-merhyl-9m-brom0-1 1B,]7a-dihydr0xy-21-acet0xy- 4-pregnene-3,20-dione To a stirred solution of 0.50 gram (1.24 millimole) of 2-methyl-l7u-hydroxy-2l acetoxy 4,9(11) pregnadiene-3,20-dione in twenty milliliters of methylene chloride was added a solution of one milliliter of 71 percent perchloric acid, in ten milliliters of water, and 206 milligrams (1.49 millimole) of N-bromoacetamide in fifty milliliters of tertiary butyl alcohol. The solution was maintained at room temperature for fifteen minutes and then mixed wtih a solution of 0.25 gram of sodium sulfite in twelve mililliters of water. The mixture was distilled at reduced pressure until the residual solution became cloudy. The product was then precipitated there? from by the addition of milliliters of a mixture of ice and water. The white, crystalline precipitate of 2,- methyl-9u-bromo-l1fi,17a dihydroxy 21 acetoxy 4- pregnene-3,20-dione was filtered, washed with water and then dried, at room temperature under vacuum. The dry product weighed 0.57 gram, a yield of 92.2 percent of the theoretical, and melted at to degrees centigrade. A sample recrystallized from a mixture of acetone and Skellysolve B hexane hydrocarbons melted at 128 to 131 degrees centigrade and had the analysis below:

Calculated for C H BrO 16.27; 16.06.

Following the procedure described in Preparation 11, but substituting another 21-ester of a 2-lower-alkyl-17a,21- dihydroxy-4,9(11)-pregnadiene-3,20-dione, e. g., a 2- ethyl 17oz hydroxy 21 acyloxy 4,9(11) pregnadiene-3,20-dione wherein the acyl radical is that of a carboxylic acid named in the paragraph following Prepa ration 6, especially those of hydrocarbon carboxylic acids containing from one to twelve carbon atoms, inclusive, as the starting steroid in the reaction, there are produced other 2l-esters of 2-methyl-9a-bromol1p],17a,2l-trihy droxy-4-pregnene-3,20-dione and 2-lower-alky1 homologues thereof.

Br, 16.07. Found: Br,

enemas l3 PREPARATZON 12 A mixture of 0.47 gram (0.95 mfllimole) of 2-methyl- 9a brorno 11,8,l7a dihydroxy 21 acetoxy 4 pregnene-3,20-dione, 0.47 gram of anhydrous potassium acetate and twenty milliliters of acetone was heated at its refluxing temperature for five hours. The coo-led mixture was poured into water and then extracted with methylene chloride. The methylene chloride extract was dried and then poured over a column of 25 grams of Florisil synthetic magnesium silicate. The column was developed with Skellysolve B hexane hydrocarbons containing increasing proportions of acetone. The Skellyso-lve B plus ten percent acetone eluates contained 0.29 gram, a yield of 75 percent of the theoretical, of 2-methyl-9:11-,8- oxido 17a hydroxy 21 acetoxy 4 pregnene 3,20- dione which, when recrystallized from a mixture of acetone and Skellysolve B hexanes, was obtained as colorless plates melting at 185 to 188 degrees centigrade, having a [@1 of plus 49 degrees in chloroform, and having the analysis below:

Calculated for C I-1 C, 69.20; H, 7.75. Found: C, 69.28; H, 7.90.

Following the procedure described in Preparation 11, but substituting another 21-ester of a 2-lower-alkyl-9abromo 11,8,17a,2l trihydroxy 4 pregnene 3,20- dione, e. g., a 2-methyl-9a-bromo-1 1,6,l7or-dihYdIOXY-2lacyloxy-4-pregnene-3,20-dione wherein the acyl radical is that of a carboxylic acid named in the paragraph follow ing Preparation 6, especially those of hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, as the starting steroid in the reaction, there are produced other 21-esters of 2-methyl-9rll-fi-oxido- 17:1,21 dihydroxy 4 pregnene 3,20 dione and 2- loWer-alkyl homologues thereof.

PREPARATIUN 13 millimoles) of 2-methylexcess of cold aqueous five percent sodium bicarbonate solution. The methylene chloride layer was separated, dried with anhydrous sodium sulfate and then poured over a column of 100 grams of Florisil synthetic magnesium silicate. The column was developed with ZOO-milliliter portions of Skellysolve B plus ten percent acetone. The eighth through sixteenth eluate fractions contained 0.61 gram of 2-II16ll1yl-9zxfiLlOIO-l1,8,l7a-dlhY- droxy-21-acetoxy-4-pregnene-3,20-dione which after crystallization from a mixture of acetone and Skellysolve B hexanes melted at 218 to 222 degrees centigrade with decomposition. A portion recrystallized from the same solvent melted at 225 to 228 degrees centigrade with decomposition, had a [0:1 of plus 156 degrees in dioxane, 21

alcohol h an.

e=l5,850, and the analysis below:

Calculated for C H FO C, 66.03; H, 7.62; F, 4.35. Found: C, 65.62; H, 7.54; F, 3.87.

Following the procedure described in Preparation 13, but substituting another 21-ester of a 21-lower-alkyl-9: 11- B oxido 170:,21 dihydroxy 4 pregnene 3,20- dione, e. g., a 2-methyl-9:l1-fi-oxido-l7ot-hydroxy-21- acyloxy-4-pregnene-3,ZO-dione wherein the acyl radical is that of an organic carboxylic acid named in the para- 14 graph following Preparation 6, especially those of a byd rocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, as the starting steroid in the reaction, there are produced other 21-esters of Z-me'thyl- 9oz fluoro 1lB,l'/a,2l trihydroxy 4 pregnene 3,20- dione and 2-lower-a1kyl ho-mologues thereof.

Following the procedure described in Preparation 13, but subst1tuting a molar equivalent amount of hydrogen chloride for the hydrogen fluoride used therein, produces 2 methyl 9a chloro 11 8,1705 dihydroxy 21 acetoxy 4 pregnene 3,20 dione. Substituting another 2 methyl 9:11 8 oxido 17a hydroxy 21 acyloxy-4-pregnene-3,20 dione, e. g., one named above, in the reaction with hydrogen chloride is productive of other 2 methyl 9a chloro 11,8,l7a dihydroxy 21 acyloxy-4-pregnene3,20-diones.

PREPARATION 14 A solution of 437 milligrams of 2-methyl-9tx-fluoro- 116,17 dihydroxy 21 acetoxy 4 pregnene 3,20- dione is freed of oxygen by bubbling nitrogen therethrough. A solution of 404 milligrams of potassium bicarbonate in four milliliters of water is similarly freed of oxygen. The two solutions are mixed at a temperature between eighteen and twenty degrees centigrade in a nitrogen atmosphere. The mixture is stirred at room temperature for five hours while protecting it from atmospheric oxygen with nitrogen. At the end of this time the solution is neutralized with glacial acetic acid. The neutral solution is concentrated by distillation at room temperature and reduced pressure and then chilled in a refrigerator for sixteen hours. The precipitated 2- methyl 9a fluoro llfi,lc,2l trihydroxy 4 pregnene-3,20-dione is filtered and dried.

2 methyl 9a fluoro 11B,17a,21 trihydroxy 4- pregnene-3,20-dione is converted to other 2-methyl-9ozfluoro 11 8,1711 dihydroxy 21 acyloxy 4 pregnene- 3,20-diones by esterification of the 2l-hydroxy group, e. g., by reaction with the appropriate acid anhydride, acid chloride or bromide, ester by ester exchange, acid in the presence of an esterification catalyst, etc. Examples of 2 methyl 9a fiuoro dihydroxy 21 acylinclude those wherein the acyl group is the acyl radical of, for example, a lower-aliphatic acid, e. g., formic, propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, Z-methylbutyric, 3-ethylbutyr1c, hexan'oic, dlethylacetic, triethylacetic,

hydroxyetiocholanic, cyclopropylideneacetic, a cycloaliphatic acid, e. g., cyclopentylformic, cyclopentylacetic, ,6 cyclopentylpropionic, cyclohexylformic, cyclohexylacetic, ,B-cyclohexylpropionic, an aryl or alkaryl acid, 6. g., benzoic, 2, 3, or 4-methylbenzoic, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylbenzoic, ethylbenzoic, 2,4,6- trimethylbenzoic, 2,4,6-triethylbenzoic, a-naphthoic, 3- methyl-a-naphthoic, an aralkyl acid, e. g., phenylacetic, phenylpropionic, diphenylacetic, triphenylacetic, a dibasic acid (which can be converted to water soluble, e. g., sodium, salts), e. g., succinic, glutaric, a-methylglutaric, B-methylglutaric, ,8,B-dimethylglutaric, adipic, pimelic, suberic, a hydroxyacid, e. g., glycolic, lactic, citric, tartaric, d-maleic, d-glyceric, mannonic, gluconic, salicyclic, an amino-acid, e. g., glycine, diglycolamic, triglycolamic, methylglycine, dimethylglycine, diethylglycine, para-aminosalicyclic, para-aminobenzoic, other heterosubstituted acids, e. g., ethylmercaptoacetic, benzylmercaptoacetic, cyanoacetic, chl'oroacetic, fiuoroacetic, trichloroacetic, trifluoroacetic, thioglycolic, 2,3,4-trimethoxybenzoic, a naphthoxyacetic, p pyrrolidylpropionic, carbamic acids, e. g., carbamic acid, phenylcarbamic, n butylcarbamic, dimethylcarbamic, diethylcarbamic,

' indole-2-carboxylic, 6-hydroxyindolyl-3-acetic, N-methylmorpholyl-Z-carboxylic, lysergic, pyrrolyl-Z-carboxylic, or other acyl acid.

PREPARATION 15 2 methyl 9oz fiuoro 17a: hydroxy 21 acetoxy 4- pregnene 3,11,20 trione To a stirred solution of 174 milligrams (0.004 mole) of 2 methyl 9a fluoro 115,170: dihydroxy 21- acetoxy-4-pregnene-3,20-dione, dissolved in 11.9 milliliters of glacial acetic acid and thereafter cooled to fourteen degrees centigrade, is added dropwise, over a period of twenty minutes, a solution of 0.55 gram of chromium trioxide, dissolved in 1.1 milliliter of glacial acetic acid and 1.1 milliliter of water. The temperature of the stirred solution is thereafter allowed to rise to eighteen degrees Centigrade over a period of one hour. The excess chromium trioxide is destroyed by the addition of an aqueous sodium sulfite solution, and the product then extracted from the reaction mixture with three fifteenmilliliter portions of ether which are thereafter combined, washed with water, and dried over anhydrous sodium sulfate. The ether is then removed by evaporation. The residue consists essentially of 2-methyl-9ot-fiuoro-17tx-hydroxy-Z1-acetoxy-4-pregnene-3,11,20-trione, which is purified by chromatographing over a column of ten grams of Florisil synthetic magnesium silicate. Developing the column with Skellysolve B hexane hydrocarbons containing increasing proportions of acetone elutes essentially pure 2 methyl 9a fiuoro 17a hydroxy 21- acetoxy-4-pregnene-3,l1,20-trione from the column.

Similarly, other 21-organic carboxylic acid esters of 2- lower alkyl 17a hydroxy 21 acyloxy 4 pregnene- 3,11,20 trione and 2 lower-alkyl 9oz halo 17ahydroxy 21 acyloxy 4 pregnene 3,11,20 trione, preferably wherein the lower-alkyl group is methyl, are prepared by oxidation of the corresponding 2l-ester of 2 lower alkyl 170:,21 dihydroxy 4 pregnene- 3,20-dione, and 2-lower-alkyl-9a-halo-17a,21-dihydroxy- 4-pregnene-320-dione, preferably the esters named in the paragraph following Preparation 6, especially those wherein the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

PREPARATION 16 2 methyl 1 1 18,] 711,21 trihydroxy 4 pregnene 3,20- dione A solution of three grams of 2-rnethyl-11fi,17a,21-trihvdroxy-4-pregnene-3,20-dione 2l-acetate, dissolved in 150 milliliters of methanol, was freed from oxygen by bubbling nitrogen gas through the solution for a period of five minutes. A solution of 1.4 grams (0.014 mole) of potassium bicarbonate was similarly purged of oxygen and mixed thereupon with a steroid solution. The resulting mixture was stirred in a nitrogen atmosphere for a period of five hours. Thereafter a solution of two milliliters of acetic acid and fifty milliliters of water was added and the mixture concentrated at reduced pressure to approximately 75 milliliters of volume. After refrigerating overnight the crystals were collected, washed with water, and dried under vacuum to give 2.25 grams (85.6 percent yield) of 2-methyl-11B,17a,21-trihydroxy- 4-pregnene-3,20-di0ne of melting point 233 to 239 degrees. This material was recrystallized from acetone to give pure 2 methyl 11fi,17a,21 trihydroxy 4 pregnene 3,20- dione of melting point 237 to 238 degrees,

e==15,250; [M plus 185'degrees (95 percent ethanol).

Analysis.-Calcd. for G i-1 C, 70.18; H, 8.57. Found: C, 70.14; H, 8.61.

-In the same manner as shown in Preparation 16, 2-

16 ethyl 11B,17a,21-trihydroxy 4 5 pregnene 3,20- dione 2l-acetate, was hydrolyzed with potassium bicarbonate in ethanol solution under exclusion of oxygen as described in the beforementioned example to give 2ethyl- 11B,17a,21-trihydroxy-4-pregnene-3,20-dione.

PREPARATION 17 fluoro 17oc,21 dihydroxy 4 pregnene- 3,11,20 lrione In the same manner as shown in Preparation 16, 2- methyl 9m fluoro 17a hydroxy 21 acetoxy 4- pregnene-3,11,2D-trione was hydrolyzed with potassium bicarbonate in aqueous methanol solution in a nitrogen atmosphere to give 2-methyl-9ot-fluoro-17a,2l-dihydroxy- 4-pregnene-3 ,1 1,20-trione.

PREPARATION 18 9oz bromo 115,17a,21 trihydroxy 4- pregitene 3,20 dione 2 methyl 9a 2 methyl A solution of one gram of 2-methyl-9ot-bromo-115,1711,- 21-trihydroxy 4 pregnene 3,20 dione Ill-acetate in 100 milliliters of dioxane was treated with one milliliter of sulfuric acid, dissolved in five milliliters of water. The reaction mixture was maintained 48 hours at room temperature, about 25 degrees centigrade, and thereupon poured onto 100 grams of ice. The resulting aqueous solution was filtered and the precipitate was recrystallized from acetone-Skellysolve B hexanes to give pure 2- methyl bromo 11B,l7a,21 trihydroxy 4- pregnene-3,20-dione.

In the same manner as shown in Preparation 18, hydrolysis of 2-methyl-9tx-chloro-11;3,l7ct,2l-trihydroxy-4- pregnene-3,20-dione 21-acetate or other 21-acylates such as named following Preparation 6 in an acidic medium provides 2 methyl 90c chloro 1lpl,17ot,2l trihydroxy-4-pregnene-3,20-dione. For the acidic medium instead of dioxane and sulfuric acid, methanol, ethanol, acetone, tertiary butyl alcohol and other organic solvents may be used together with sulfuric, hydrochloric, perchloric, chloric, or para-toluene-sulfonic acid can be used.

Similarly, other 2-methyl-11 p,17a-dihydro-xy-21-acyloxy-4-pregnene-3,20-diones wherein the acyl group is the acyl radical of, for example, a lower-aliphatic acid such as formic, propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, Z-methylbutyric, B-ethylbutyric, hexanoic, diethylacetic, triethylacetic, heptanoic, octanoic, benzoic, 2, 3, or 4-methyl-benzoic, ,B-cyclopentylpropionic, phenylacetic, phenylpropionic, a dibasic acid (which can be converted to water soluble, for example, sodium salts), for example, succinic, glutaric, adipic, suberic, tartaric, citric, halogenated acids, such as chloroacetic, dichloroacetic fiuoroacetic, trichloroacetic, trifiuoroacetic, or the like, are converted to the corresponding 2 methyl 11fi,170c,21 trihydroxy 4-pregnene-3,20- diones.

In the same manner as shown in Preparations 16 thru 18, other 2 loWer-alkyl-l1{3,17ot-dihydroxy-2l-acyloxy-4- pregnene-3,20-diones wherein the lower-alkyl group may be methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, phenyl, or benzyl, or the like, and wherein the acyloxy group is any of the above mentioned acyloxy groups, can be converted to the corresponding 2-loweralkyl-l1,B,17 (1,21-trihydroxy-4-pregnene-3 ,20-diones.

EXAMPLE 1 21-toluenesulf0nate 0 2-methyl-11fi,17a,21- trihydr0xy-4-pregnene-3,ZO-dione 17 quired ten minutes after which the solution was refrig erated to plus five degrees centigrade for a period of 18 hours. The solution was thereupon poured into water large quantity of methylene chlo- The combined extracts were Washed with cold five acid solution to remove pyridine, then with cold five percent sodium bicarbonate solution, and thereafter with water. After drying the solution over anhydrous sodium sulfate the extract was evaporated at reduced pressure, to give a residue of 2l-toluenesulfonate of 2-methyl-1 15,17a,21-trihydroxy-4-pregnene-3 ,20-dione;

EXAMPLE 2 2-ethyl-1],8,] 701,21-trihydroxy-4-pregnene-3,20- dione-21-methanesulf0nate In the same manner as shown in Example 1, substituting the 2 methyl-11/3,17u,2l-trihydroxy-4-pregnene-3,20- dione by 2-ethyl-l1,8,17a,21-trihydroxy-4-pregnene-3,20- dione and the toluenesulfonyl chloride by methanesulfonyl chloride produces a ZI-methanesulfonate of 2-ethyl- 1 13, 1 711,2 1 -trihydroxy-4-pregnene-3,20-dione.

EXAMPLE 3 In the samernanner as shown in Example 1, treating 2- methyl-9a-fluoro-l7a,21-dihydroxy-4 pregnene 3,11,20- trio ne with toluenesulfonyl chloride yields the ll-toluenesulfonate of 2 methyl 9a fiuoro 'l7a,'21-dihydroxy-4- pregnene-3 ,11,20-trione.

In the same manner as Examples 2, 3, and 4, other 2- lower-alkyl llfi,l7oz,2l trihydroxy 4 pregnene 3,20- dione '2l-toluenesulfonates, benzenesulfonates, methanesulfonates, vfi-naphthylsulfonates, and the like, may be produced wherein the lower-alkyl groups are methyl, ethyl, propyl, isopropyl, hutyl, isobutyl, pentyl, hexyl, benzyl, or ,phenyl, and wherein the Qua-position may be substituted by a halo atom having an atomic weight between 17 and 13.1.

EXAMPLE 5 Z-methyl-IJBJ 7a-dihydr0xy-4-pregnene 3,ZO-dione Thecrude 2l-toluenesulfonate of Z-methyl-l 1,6,17a,21- trihydroxy-4-pregnene-3,20Tdione, as obtained in Example l, was dissolved in '1 O0-milliliters of warm acetone and treated with a solution of -four grams of sodium iodide, dissolved in fifty milliliters of acetone. The mixture was stirred under reflux for fifteen minutes and then evaporatedat reduced pressure to give'crude 2-methyl- 11,8,17-a-dihydroxy-21-iodo-4apregnene-3,20-dione.

The crude 2 methyl --1 1 6,170: dihydroxy 21-iodo-4- pregnene-3,20-dione was slurried with fifty milliliters of acetic acid, and stirred for-45 minutes. Thereupon was added three grams of zinc dust-and-the mixture was stirred for anotherzfifteen minutes at room temperature (about 22 degrees 'centigrade) The reaction mixture was thereupon filtered .to removethe excess of zinc and the zinc particles on the filter were washed with ten milliliters of acetic acid and thereupon with methylene chloride, The. combined filtrate and washings were diluted with water and extracted with a large quantity of methylene chlo ride. The thus-obtained methylene chloride extracts'were washed with cold five percent sodium bicarbonate solution until neutral, then with water and finally dried over anhydrous sodium sulfate. After evaporation of the-solvent at reduced pressure, a crystalline residue was obtained which was recrystallized from acetone repeatedly to give pure 2-methyl 1'1p,17a dihydroxy-4-pr'egnene- 3,20-dione of melting point 260 to 264.

Analysis.-Calcd. for C H O C, 73.30; H, 8.955 Found: c, 72.9 H, 9.02.

EXAMPLE 6 EXAMPLE 7 Z-ethyl-I I 8,] 7a-dihydroxy-4 pregnelre-3,20-alione In the same manner as given in Example 5, '-2'-ethyll1,3,17a,21-trihydroxy-4-pregnene-3,20-dione 21-methanesulfonate was dissolved in acetone and treated with p0- tassium iodide ,to give the corresponding 2 ethyl l 1=}3, 17adihydro-xy-Zl-iodo-4-pregnene-3,ZO-dione. The Z-ethyl- 11/3,l7a-dihydroxy-21-iodo 4 pregnene-3,20-dione was dissolved in dioxane containing five, percent of water'and thereupon was added a large excess of sodium hydrosu l in Example 5, '2-methy1 sponding .2-lower-alkyl-.11B,17a-dihydroxy 4 pregnene- 3,20-dione.

EXAMPLE 8 Z-methyl-9a-fluoro-4-pregnene-3,11,20-trione The 21-toluenesulfonate o-f 2-methyl-9a-flu0ro-17 21-- dihydroxy-4-pregnene-3,l1,20-trione of EXample 4, was dissolved in acetone-and treated with a solution of sodium iodide and acetone as shown-in Example '5 t0 g i Ye the corresponding 2-methyl-9a-fluoro a -':hydroxy-21- iodo 4 pregnene 3,11,20 trione. Reduction of the 2-methyl-9a-fluoro-17a-hydroxy 21 iodo 4 pregn ene- 3,11,20-trione with .Zinc and .acetic acid' was productive of the corresponding ,2-methyl-9n-fluoro-11a-hydroxy 4- pregnene-3,11,20-trione.

In a manner similar to Example 8,;other 2?lower;all;yl-, Set-halo -17a-hydroxy-4-pregnene-3, 1 1,20-triones -,-;-are pr e pared by converting the corresponding lower-alkyl-9uhalo-l'ia-hydroxy-2l-toluenesulfonyloxy 4 pregnene- 3,11,20-triones to the corresponding Zl-iodo compounds and reducing these iodo compounds with a reducing agent such as zinc and acetic acid, sodium or potassium sulfite, sodium or potassium hydrosulfite, sodium or potassium thiosulfate, or the like.

EXAMPLE 9 Z-methyl-I 7a-hydroxy4-pregnene-3,11,20-trione EXAMPLE Z-ethyl-I 7a-hydr0xy-4-pregnene-3J1,20-trione In the same manner as given in Example 9, Z-ethyll1B,l7a-dihydroxy-4-pregnene-3,11,20-trione is oxidized with chromiciacid in acetic acid solution to give the corresponding 2-ethyl-17a-hydroxy 4 pregnene 3,11,20- trione.

' EXAMPLE 11 2-methyl-9a-chl0ro-1 7a-h ydroxy-4-pregnene-3 ,1 1,20-

trione In the same manner as given in Example 9, 2methyl- 9a chloro-l1B,l7a-dihydroxy-4-pregnene-3,ZO-dione was oxidized with chromic anhydride in acetic acid solution to give 2-methyl-9e-chloro-Hot-hydroxy 4 pregnene- 3,11,20-trione.

EXAMPLE 12 A solution of 2-methyl-9u-fiuoro-11fi,17a-dihydroxy-4- pregnene-3,ll,20-trione in benzene was vigorously stirred with a solution of potassium dichromate in water containing for each part of steroid in the benzene layer one half to one part of potassium dichromate together with one and one-half parts of sulfuric acid. The stirring of the mixture was continued for a period of six hours at room temperature, about 25 degrees centigrade, whereupon the benzene layer was separated from the water layer, washed with sodium bicarbonate and water, and dried over anhydrous sodium sulfate. Thereafter the dry benzene layer was evaporated and the residue recrystallized from acetone Skellysolve B hexanes to give pure 2-methyl-9c-fluoro-Nix-hydroxy 4 pregnene 3,11,20- trione.

In the same manner as shown in Examples 9 through 12, inclusive, other 2-lower-alkyl-l1)3,17a-dihydroxy-4- pregnene-3,20-diones which may further be substituted in the 9a-position by fluoro, chloro, bromo, or iodo atoms are oxidized in chromic acid to give the corresponding 2 lower-alkyl-17a-hydroxy 4 pregnene-3,11,20-trione wherein the lower-alkyl group is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, benzyl, and phenyl.

EXAMPLE 13 2-methyl-1 15,17a-diacet xy-4-pregnene-3,ZO-dione One half gram of 2-methyl-11fi,l7a-dihydroxy-4-pregnone-3,20-dione was dissolved in twenty milliliters of acetic anhydride. Thereto was added 0.2 gram of paratoluenesulfonic acid monohydrate and the mixture was the like.

heated to reflux for a period of five hours. Thereafter the mixture was poured into 200 milliliters of ice water and the mixture was extracted with three fifty-milliliter portions of methylene chloride. The methylene chloride extracts were washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo. The solid residue was recrystallized from methanol to' give pure Z-methyl-l1B,17a-diacetoxy-4-pregnene-3,20-dione.

In a manner similar to Example 13, esterifying the 2-lower-alkyl-1l-oxygenated-lh-hydroxy 4 pregnene- 3,20-diones obtained in the prior examples by refluxing these compounds with hydrocarbon carboxylic acid anhydrides or isopropenyl acylate in the presence of a strong acid catalyst produces other 17OL-I11OI10- and 11B, l'la-di-esters of such 2-alky1-l1-oxygenated-17a-hydroxy- 4-pregnene-3,20-diones. Such mono and di-esters illustratively comprise: 2-methyl-1lB,17a-dipropionyloxy-4 pregnene-3,20-dione, Z-methyl 11 3,17 dibutyryloxy-4- pregnene-3,20-dione, Z-methyl 9a fluoro 1lp,17a divaleryloxy 4 pregnene3,20-dione, 2-methyl-9u-fluoro- 113,170: dibenzoyloxy-4-pregnene-3,ZO-dione, Z-methyl- 17a-acetoxy 4 -pregnene-3,ll,20-trione, 2-methyl-17apropionyloxy 4 pregnene-3,11,20-trione, 2-methyl-17w butyryloxy-4-pregnene-3 ,1 1 ,ZO-trione, 2-methyl-9 a-fi11010- 17a acetoxy 4 pregnene-3,l1,20-trione, 2-methyl-9afluoro-17a-valeryloxy-4-pregnene-3,l 1,20-trione, Z-methyl- 9a-fiuoro-l7a-capryloxy 4 pregnene 3,11,20 trione, 2-methyl-9a-fluoro-17a-benzoy1oxy 4 pregnene-3,11,20- trione, 2 ethyl-l118,1'le-diacetoxy-4-pregnene-3,ZO-dione, 2 ethyl-11,9,17a-dihexanoyloxy-4-pregnene-3,ZO-dione, or These esters have activity like the free alcohols and often more enhanced than the free alcohols from which they have been derived and can also be substituted for the free alcohols in the before-mentioned compositions.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1 2-methyl-1 1 B,17u-dihydroxy-4-pregnene-3 ,20-dione.

2. 2 methyl 9oz fluoro 1119,1711 dihydroxy 4- pregnene-3,20-dione.

3. Z-methyl-l7u-hydroxy-4-pregnene-3,11,20-trione.

4. 2 methyl 9a fluoro 17o: hydroxy 4 pregnene-3 ,1 1 ,ZO-trione.

5. 2-ethyl-1118,l7m-dihydroxy-4-pregnene-3,ZO-dione.

6. A process for the production of a 2-lower-alkyl-11- oxygenated 17a hydroxy 4 pregnene 3,20 dione which comprises: treating a 2-lower-alkyl-ll-oxygenated- 17:1,21-dihydroxy-4-pregnene-3,ZO-dione selected from the group consisting of 2-lower-alkyl-1lp,17a,21-trihydroxy 4 pregnene 3,20 dione, 2 lower alkyl- 17a,21 dihydroxy 4 pregnene 3,11,20 trione, 2- lower alkyl 9a halo 115,17a,21 trihydroxy 4- pregnene 3,20 dione, 2 loweralkyl-9u-halo-l7a,2ldihydroxy-4-pregnene-3,11,20-tri0ne wherein the halo atom has an atomic weight between 17 and 131 and the lower-alkyl radical contains from one to eight carbon atoms, inclusive, with an organic acid sulfonyl chloride selected from the group consisting of toluenesulfonyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, naphthylsulfonyl chloride to give the correspond ing 11-oxygenated-2-lower-alkyl-17u-hydroxy-21-organic acid sulfonyloxy-4-pregnene-3,ZO-dione; heating the thus obtained ll-oxygenated 2-lower-alkyl-17a-hydroxy-21- organic acid sulfonyloxy-4 pregnene-3,20-dione in acetone solution with alkali iodide to obtain the corresponding 11oxygenated 2-lower-alkyl-17m-hydroxy-2l-iodo-4-pregnene-3,20-dione and treating the thus obtained 21-iodo steroid with a reducing agent selected from the group consisting of zinc dust and acetic acid, an alkali metal thiosultate, an alkali metal sulfite and an alkali metal hydrosulfite to give the corresponding ll-oxygenated 2- lower-alkyl-l7a-hydroxy-4-pregnene-3,20-dione.

7. A process for the production of 2-methyl-ll/3,17adihydroxy 4 pregnene 3,20 dione which comprises: treating 2 methyl 11B,l7oc,21 trihydroxy 4 pregnene-3,20-dione with toluenesulfonyl chloride to obtain the corresponding Z-methyl-l1p,17a-dihydroxy-2l-toluenesulfonyloxy-4-pregnene-3,20-dione, reacting the thus obtained 2-methyl-1173,17a-dihydroxy-2l-toluenesulfonyloxy- 4-pregnene-3,20-dione with an alkali metal iodide in acetone to give 2-methyl-11,8,17a-dihydroxy-21-iodo-4-preg= nene-3,20-dione and reducing the thus obtained steroid 21- iodide with zinc and acetic acid to give 2-methyl-11,B,17ocdihydroxy-4-pregnene-3,20-dione.

8. A process for the production of 2-rnethyl-9a-fluoro 115,170; dihydroxy 4 pregnene 3,20 dione which comprises: treating 2-methyl-9a-fluoro-l lfi,17 x,21-trihydroXy-4-pregnene-3,20-dione with toluenesulfonyl chloride to obtain the corresponding 2-methyl-9wfluoro- 115,170: dihydroxy 21 toluenesulfonyloxy 4 pregnene-3,20-dione, reacting the thus obtained 2-methy1-9ufluoro 115,170 dihydroxy 21 toluenesulfonyloxy 4- pregnene-3,20-dione with an alkali metal iodide in acetone to give 2-methyl-9a-fluoro-l1p,l7a-dihydroxy-21-iodo-4- pregnene-3,20-dione and reducing the thus obtained steroid 2l-iodide with zinc and acetic acid to give 2-methyl-9ufluoro-l118,17u-dihydroxy-4-pregnene-3 ,20-dione.

9. A process for the production of 2-methyl-17u-hydroxy-4-pregnene-3,l1,20-trione which comprises: treating 2 methyl 11,8,17a,2l trihydroxy 4 pregnene- 3,20-dione with toluenesulfonyl chloride to obtain the corresponding 2-methyl-1lB,17a-dihydroxy-2l-toluenesulfonyloxy-4-pregnene-3,20-dione, reacting the thus obtained 2 methyl 116,170: dihydroxy 21 toluenesulfonyloxy-4-pregnene-3,20-dione with an alkali metal iodide in acetone to give 2-methyl-1l 8,l7a-dihydroxy-2l-iodo-4- pregnene-3,20-dione, reducing the thus obtained steroid 2l-iodide with zinc and acetic acid to give 2-methyl- 11,8,17a-dihydroXy-4-pregnene-3,20-dione and oxidizing the thus obtained 2-methyl-l1,8,17a-dihydroxy-4-pregnene- 3,20-dione with chromic acid to obtain 2-methyl-l7a-hydroxy-4-pregnene-3,1 1,20-trione.

process for the production of 2-methyl-9afluoro-l lu-hydroxy-4-pregnene-3,l 1,20-trlone which comprises: treating 2-methyl-9a-fluoro-1l,8,l7a,2l-trihydroxy- 4-pregnene-3,20-dione with toluenesulfonyl chloride to obtain the corresponding 2-methyl-9a-fluoro-ll 3,l7a-di hydroxy-21-toluenesulfonyloxy-4-pregnene-3,20-dione, reacting the thus obtained 2-methyl-9a-fiuoro-l1,8,17a-dihydroxy 21 toluenesulfonyloxy-4-pregnene-3,ZO-dione with an alkali metal iodide 90: fluoro 11,8,l7oc dihydroxy 21 iodo-4-pregnene- 3,20-di0ne, reducing the thus obtained steroid 2l-iodide with zinc and acetic acid to give 2-methyl-9a-fluoroin acetone to give 2-methylv 12. 2 lower-alkyl 11fl,17oc dihydroxy-4-pregnene- 3,20-dione, wherein the lower-alkyl radical contains from one to eight carbon atoms, inclusive.

l3. 2 lower alkyl-l7u-hydroxy-4-pregnene3,l1,20- trione, wherein the lower-alkyl radical contains from one to eight carbon atoms, inclusive.

14. 2 lower alkyl-9a-fluoro-l1B,17a-dihydroxy-4- pregnene-3,20-dione, wherein the lower-alkyl radical con- 25 tains from one to eight carbon atoms, inclusive.

15. 2 lower alkyl-9a-fluoro-17a-hydroxy-4-pregnene- 3,11,20-trione wherein the lower-alkyl radical contains from one to eight carbon atoms, inclusive.

16. A compound represented by the formula wherein R is hydrogen, R is fi-hydroxy and together R and R is oxygen and X is selected from the group consisting of hydrogen and fluorine.

References Cited in the file of this patent 5 UNITED STATES PATENTS 2,707,190 Farrar Apr. 26, 1955 2,708,673 Levin May 17, 1955 2,744,110 Ralls May 1, 1956 OTHER REFERENCES Fried: J. Am. Chem. Soc. 75, 2273 (1953). Fried: J. Am. Chem. Soc. 76, 1544-6 (1954). 

6. A PROCESS FOR THE PRODUCTION OF A 2-LOWER-ALKYL-11OXYGENATED- 17A-HYDROXY-4-PREGNENE-3,20-DIONE WHICH COMPRISES: TREATING A 2-LOWER-ALKYL-11-OXYGENATED17A,21-DIHYDROXY-4-PREGENE-3,20-DIONE SELECTED FROM THE GROUP CONSISTING OF 2-LOWER-ALKYL-11B,17A,21-TRIHYDROXY-4-PREGENE-3,20-DIONE, 2-LOWER-ALKYL17A,21-DIHYDROXY-4-PREGENE,-3,11,20-TRIONE, 2LOWER-ALKYL-9A-HALO-11B,17A,21-TRIHYDROXY-4PREGENE-3,20-DIONE, 2-LOWER-ALKYL-.A-HALO17A,21DIHYDROXY-4-PREGENE-3,11,20-TRIONE WHEREIN THE HALO ATOM HAS AN ATOMIC WEIGHT BETWEEN 17 AND 131 AND THE LOWER-ALKYL RADICAL CONTAINS FROM ONE TO EIGHT CARBON ATOMS, INCLUSIVE, WITH AN ORGANIC ACID SULFONYL CHLORIDE SELECTED FROM THE GROUP CONSISTING OF TOLUENESULFONYL CHLORIDE, BENZENESULFONYL CHLORIDE, METHANESULFONYL CHLORIDE, NAPHTHYLSULFONYL CHLORIDE TO GIVE THE CORRESPONDING 11-OXYGENATED-2-LOWER-ALKYL-17A,-HYDROXY-21-ORGANIC ACID SULFONYLOXY-4-PREGNENE-3,20-DIONE; HEATING THE THUS OBTAINED 11-OXYGENATED 2-LOWER-ALKYL-17A-HYDROXY-21ORGANIC ACID SULFONYLOXY-4-PREGNENE-3,20-DIONE IN ACETONE SOLUTION WITH ALKALI IODIDE TO OBTAIN THE CORRESPONDING 11-OXYGENATED 2-LOWER-ALKYL-17A-HYDROXY-21-IODO-4-PREGNENE-3,20-DIONE AND TREATING THE THUS OBTAINED 21-IODO STEROID WITH A REDUCING AGENT SELECTED FROM THE GROUP CONSISTINF OF ZINC DUST AND ACETIC ACID, AN ALKALI METAL THIOSULFATE, AN ALKALI METAL SULFITE AND AN ALKALI METAL HYDROSULFITE TO GIVE THE CORRESPONDING 11-OXYGENATED 2LOWER-ALKYL-17A-HYDROXY-4-PREGNENE-3,20-DIONE.
 16. A COMPOUND REPRESENTED BY THE FORMULA 